The hypoxia inducible factor HIF-1 alpha is ubiquitously expressed but undergoes proteosomal degradation under normal oxygen conditions. However, because the skin is naturally hypoxic, HIF-1 alpha is stably expressed and detectable by immunohistochemistry in the epidermis and hair follicle. We have observed that mice in which HIF-1 alpha has been deleted postnatally develop skin lesions that are characterized by epidermal thickening and hair loss. Recent research has shown that HIF-1 alpha regulates p21 expression in keratinocytes, and correlates with cell cycle arrest in cultured keratinocytes in vitro. This proposal will test the following hypothesis: HIF-1 alpha plays an essential role in regulating keratinocyte proliferation and differentiation in vivo in a c-Myc dependent manner. To test this hypothesis, we will (1) determine the role of HIF-1 alpha in the epidermis and (2) determine the mediators of epidermal HIF-1 alpha activity, focusing on c- Myc. The proposed experiments will allow us to conduct initial investigations into the role of HIF-1 alpha in keratinocytes. The overall goal of the studies is to understand the degree to which HIF-1 alpha regulates biological processes in physiological settings such as the epidermis, as well as the mechanisms by which it acts, and how this phenomenon contributes to skin growth and differentiation in both homeostasis and disease.